2. Academic Validation
  3. Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

  • J Clin Invest. 2021 Jun 1;131(11):e137845. doi: 10.1172/JCI137845.
Daria Capece 1 2,  Daniel D'Andrea 1,  Federica Begalli 1,  Laura Goracci 3,  Laura Tornatore 1,  James L Alexander 4,  Alessandra Di Veroli 3,  Shi-Chi Leow 5,  Thamil S Vaiyapuri 6,  James K Ellis 1 7,  Daniela Verzella 1,  Jason Bennett 1,  Luca Savino 1 8,  Yue Ma 4,  James S McKenzie 7,  Maria Luisa Doria 7,  Sam E Mason 7,  Kern Rei Chng 9,  Hector C Keun 7,  Gary Frost 4,  Vinay Tergaonkar 6,  Katarzyna Broniowska 10,  Walter Stunkel 5,  Zoltan Takats 7,  James M Kinross 7,  Gabriele Cruciani 3,  Guido Franzoso 1
Affiliations

Affiliations

  • 1 Department of Immunology and Inflammation, Imperial College London, London, United Kingdom.
  • 2 Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, L'Aquila, Italy.
  • 3 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
  • 4 Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
  • 5 Singapore Institute for Clinical Sciences (SICS), and.
  • 6 Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore.
  • 7 Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
  • 8 Department of Medical, Oral, and Biotechnological Sciences, "G. D'Annunzio" University of Chieti-Pescara, Chieti, Italy.
  • 9 Genome Institute of Singapore, Singapore.
  • 10 Metabolon, Inc., Morrisville, North Carolina, USA.
PMID: 33878036 DOI: 10.1172/JCI137845
Abstract

The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-κB has been shown to drive tumor-promoting inflammation, Cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated Lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from Other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

Keywords

Colorectal cancer; Metabolism; NF-kappaB; Oncology.

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